DESCRIPTION (provided by investigator): Depression is a risk factor for mortality after hospitalization for acute coronary syndrome (ACS). However, converging evidence from several recent clinical trials suggests that the mortality risk is higher among patients with treatment-resistant depression than those who respond to standard treatments for depression. Interestingly, some of the strongest predictors of treatment resistance in depressed psychiatric patients also happen to be cardiac risk markers, including indicators of cardiovascular autonomic dysregulation, HPA axis dysregulation, and proinflammatory and procoagulant processes. Furthermore, these markers have also been identified as potential mediators of the effect of depression on post-ACS mortality. The purpose of this study is to test the hypotheses that 1) depressed post-ACS patients who fail to respond to aggressive treatment for depression have higher levels of specific cardiac risk markers at the end of treatment than do otherwise comparable patients who do respond; 2) high levels of these cardiac risk markers prior to treatment predict poor response to depression treatment; and 3) these risk markers improve as depression improves in treatment responders. Participants will be recruited from three St. Louis area hospitals affiliated with Washington University School of Medicine. One hundred seventy patients, who meet the DSM-IV criteria for a current major depressive episode and who score 17 or higher on the HAM-D-17 approximately 3 months after hospitalization for ACS, will be enrolled in the study. All participants will be treated with individual cognitive behavior therapy (CBT) for up to 6 months. The frequency of CBT sessions will decrease when specific improvement criteria are met. Patients who have not improved >50 percent on the BDI-II depression questionnaire by 3 months will continue in CBT but will also be given sertraline at an initial dosage of 50 mg/day. If necessary and if tolerated, the dosage will be gradually increased to a maximum of 200 mg/day. Depression will be assessed, and cardiac risk markers will be measured, at baseline, 3 months, and 6 months. Structural equation models will be used to test the primary hypotheses. Relevance: Depression doubles the risk of death after a heart attack, for reasons that are not well understood. Initial efforts to reduce this risk by treating depression have not been successful. This study will help to clarify how depression increases the risk of dying, and it may suggest ways to develop more effective interventions. PUBLIC HEALTH RELEVANCE: Depression doubles the risk of death after a heart attack, for reasons that are not well understood. Initial efforts to reduce this risk by treating depression have not been successful. This study will help to clarify how depression increases the risk of dying, and it may suggest ways to develop more effective interventions.